Studies on tolerance. II. The effect of timing on inhibition of tolerance to morphine by cycloheximide

Abstract

Cycloheximide (CX) given 1 hour before each weekly dose of morphine inhibits the development of tolerance. The temporal relationship of the doses of CX and morphine sulfate seems to be a most important factor. CX (1 mg/kg s.c.) given 24 hours before, 6 hours before or 6 hours after weekly morphine injections (10 mg/kg s.c.) does not affect the rate or the degree of tolerance development. The inhibition of tolerance seen after weekly administration of CX plus injections of morphine is not seen until several weeks after drug treatment has begun and the difference between the morphine only and the morphine plus CX groups persists for a number of weeks after drug treatment has been terminated. The inhibition of tolerance seen after CX does not appear to be due to any nonspecific debilitating effect of CX. However, it may be related to the ability of CX to suppress protein synthesis. The identity of the proteins involved or how they are involved in the tolerance phenomenon remains unclear.